Lipid and lipoprotein metabolism and immunosuppression in cancer
Epidemiological data clearly demonstrate that patients suffering from obesity and the metabolic syndrome have a higher risk to develop cancer. For example, chronically elevated plasma insulin as well as leptin levels have been shown to favor tumor growth and progression, resulting in poor prognosis and higher mortality of obese cancer patients. Moreover, immunosuppressive myeloid cell populations accumulate in the tumor microenvironment (TME) of obese cancer patients, thereby fostering tumor growth and progression. By using syngeneic murine tumor models, biochemical and functional cell biological methods as well as immunological assays, we try to understand how metabolic perturbations in systemic lipid and lipoprotein metabolism affect the immunosuppressive behavior of myeloid cells in the TME. Specifically, we aim at the identification of novel obesity-related metabolic pathomechanisms that drive the activation and maturation of myeloid-derived suppressor cells (MDSC), thereby acquiring a highly immunosuppressive phenotype resulting in efficient inhibition of the anti-tumor T cell response.
A, Growing, vascularized tumors secrete a plethora of soluble cytokines that communicate with B, the bone marrow niche, leading to the expansion of a heterogeneous population of immature, immunosuppressive myeloid cells (myeloid-derived suppressor cells; MDSC) of granulocytic (G-MDSC) and monocytic (M-MDSC) origin. C, MDSC then home into the TME, where they suppress anti-tumor T cell responses by various mechanisms such as arginine depletion and PD-L1 expression. Obese cancer patients and tumor mice frequently exhibit a profound degree of immunosuppression in the TME. However, the promoting forces that increase the immunosuppressive micromilieu in settings of obesity and dyslipidemia remain largely unknown.
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